WO1998043965A1 - Thiodepsipeptides pour lutter contre des endoparasites et procede simple permettant de les preparer - Google Patents

Thiodepsipeptides pour lutter contre des endoparasites et procede simple permettant de les preparer Download PDF

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Publication number
WO1998043965A1
WO1998043965A1 PCT/EP1998/001628 EP9801628W WO9843965A1 WO 1998043965 A1 WO1998043965 A1 WO 1998043965A1 EP 9801628 W EP9801628 W EP 9801628W WO 9843965 A1 WO9843965 A1 WO 9843965A1
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Prior art keywords
methyl
leucinyl
alkyl
sulfur
independently
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PCT/EP1998/001628
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German (de)
English (en)
Inventor
Peter Jeschke
Achim Harder
Georg Von Samson-Himmelstjerna
Norbert Mencke
Gerhard Bonse
Katsuharu Iinuma
Osamu Sakanaka
Original Assignee
Bayer Aktiengesellschaft
Meiji Seika Kaisha, Ltd.
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Application filed by Bayer Aktiengesellschaft, Meiji Seika Kaisha, Ltd. filed Critical Bayer Aktiengesellschaft
Priority to JP54110898A priority Critical patent/JP2001524952A/ja
Priority to AU70388/98A priority patent/AU731789B2/en
Priority to DE59807652T priority patent/DE59807652D1/de
Priority to US09/381,946 priority patent/US6265537B1/en
Priority to NZ338102A priority patent/NZ338102A/xx
Priority to EP98917025A priority patent/EP0973756B1/fr
Publication of WO1998043965A1 publication Critical patent/WO1998043965A1/fr
Priority to HK00108376A priority patent/HK1029114A1/xx

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to cyclic thiodepsipeptides, in particular 18- to 24-membered cyclothiodepsipeptides, a simple process for their preparation and their use for controlling endoparasites
  • thiodepsipeptide PM-93135 which was isolated as a fermentation product from a Micromonospora strain (Actinomycetes) and antibacterial
  • Cyclothiodepsipeptides consisting of amino acids, hydroxythiocarboxylic acids and optionally hydroxycarboxylic acids as ring building blocks have hitherto not been known
  • Cyclodepsipeptides with 18 to 24 ring atoms are known as agents for combating endo-parasites (cf. eg BY Kodama et al, Be Reports of Meiji Seika Kaisha 31, 1992, pp. 1-8, EP-OS 382 173, EP-OS 503 538, WO 93/19 053, WO 94/19334, WO 95/07272, EP 626 375, EP 626 376, EP 664 297, EP 634 408, 718 298)
  • the present invention relates to new cyclic thiodepsipeptides and a process for preparing the cyclic thiodepsipeptides, consisting of amino acids, hydroxythiocarboxylic acids and optionally hydroxycarboxylic acids as ring building blocks and 18 to 24 ring atoms
  • Another subject is the use of cyclic thiodepsipeptides consisting of amino acids, hydroxythiocarboxylic acids and optionally hydroxy carboxylic acids as ring building blocks and 18 - 24 ring atoms, as a means of combating endoparasites
  • the present invention relates in particular
  • R 1 , R 4 , R 7 and R 10 independently of one another for hydrogen, straight-chain or branched C ⁇ . 4 - alkyl
  • R 2 , R 5 , R 8 and R 11 independently of one another for hydrogen, straight-chain or branched C ⁇ .g-alkyl, Ci «alkenyl, C 3 6 -cycloalkyl, C 3 6 -cycloalkyl-C ⁇ 2 - alkyl, aryl-Ci -alkyl, hetaryl -CC. 2 -alkyl, aryl or hetaryl which are optionally substituted,
  • R 9 and R 10 together with the atoms to which they are attached represent a 5- or
  • R 10 and R 11 together with the atoms to which they are attached represent a 5-, 6- or 7-membered ring which can optionally be interrupted by oxygen, sulfur, sulfoxy or sulfonyl and is optionally substituted,
  • R 3 and R 9 independently of one another for hydrogen, -8-alkyl or aryl-C ⁇ . 2 -alkyl, C 3 . 6- cycloalkyl-C,. 2 -alkyl,
  • R 6 and R 12 independently of one another for hydrogen, straight-chain or branched Ci-g-alkyl, C ⁇ . .. 8 alkenyl, C 3 (-. Cycloalkyl, C 3 6 cycloalkyl-2 C ⁇ _ alkyl, aryl C ⁇ _ 2 - alkyl, hetaryl-C ⁇ 2, aryl or hetaryl alkyl optionally substituted, are provided.
  • X 1 , X 2 , X 3 and X 4 independently of one another denote oxygen or sulfur, at least one of the radicals X 1 , X 2 , X 3 and X 4 having to stand for sulfur,
  • R to R and X to X have the meanings given under point 1, thionated in the presence of a suitable sulfurizing agent and in the presence of a suitable diluent
  • the compounds of general formula (I) can, depending on the type of
  • Cyclic thiodepsipeptides consisting of amino acids, hydroxythiocarboxylic acids and optionally hydroxycarboxylic acids as ring building blocks and 24 ring atoms, the general formulas (I) and their salts are preferred
  • R 1 , R 4 , R 7 and R 10 stand for straight-chain or branched C ⁇ _ alkyl, in particular methyl,
  • R 2 , R 5 , R 8 and R u are C M alkyl, in particular isobutyl,
  • R 3 and R 9 independently of one another for C 4 alkyl or aryl C 1.
  • X 1 means sulfur
  • X 2 , X 3 and X 4 independently of one another denote oxygen or sulfur
  • X 2 2 means sulfur
  • X 1 , X 3 and X 4 independently of one another denote oxygen or sulfur
  • X means sulfur X 1 , X 2 and X 4 independently of one another denote oxygen or sulfur,
  • X 1 , X 2 and X 3 independently of one another denote oxygen or sulfur
  • the thiodepsipeptides according to the invention and their salts are generally defined by the general formula (I).
  • thiodepsipeptides according to the invention and their acid addition salts and metal salt complexes have good endoparasiticidal, in particular anthelmintic, effects and can preferably be used in the field of veterinary medicine
  • Optionally substituted alkyl alone or as part of a radical in the general formulas means straight-chain or branched alkyl having preferably 1 to 6, in particular 1 to 4, carbon atoms.
  • Examples include optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1, 1- dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2, 3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,
  • Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl may preferably be mentioned.
  • Optionally substituted alkenyl alone or as part of a radical in the general formulas means straight-chain or branched alkenyl with preferably 1 to 6, in particular 1 to 4, carbon atoms.
  • Examples include optionally substituted vinyl, 2-propenyl, 2-butenyl, 3-butenyl, l-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, l-methyl- 2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, l-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, l, l-dimethyl-2-propenyl, l, 2-dimethyl-2-propenyl, l-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, l-methyl 2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, l-methyl-
  • Methyl-4-pentenyl l, l-dimethyl-2-butenyl, l, l-dimethyl-3-butenyl, l, 2-dimethyl-2-butenyl, l, 2-dimethyl-3-butenyl, l, 3- Dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, l-ethyl-2-butenyl, l-ethyl-3- butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, l, l, 2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and l-ethyl- Called 2-methyl-2-propenyl.
  • Optionally substituted ethenyl, 2-propenyl, 2-butenyl or 1-methyl-2-propenyl may preferably be mentioned.
  • Optionally substituted alkynyl alone or as part of a radical in the general formulas means straight-chain or branched alkynyl with preferably 1 to 6, in particular 1 to 4, carbon atoms.
  • Examples include optionally substituted ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, l-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, l-methyl-3-butynyl, 2-methyl- 3-butynyl, 1-methyl-2-butynyl, l 1-dimethyl-2-propynyl, l-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-
  • Optionally substituted ethynyl, 2-propynyl or 2-butynyl may be mentioned.
  • Optionally substituted cycloalkyl alone or as part of a radical in the general formulas means mono-, bi- and tricyclic cycloalkyl, preferably having 3 to 10, in particular 3, 5 or 7, carbon atoms. Examples are optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
  • Haloalkyl alone or as a constituent of a radical in the general formulas contains 1 to 4, in particular 1 or 2, carbon atoms with preferably 1 to 9, in particular 1 to 5 identical or different halogen atoms, preferably fluorine,
  • Chlorine or bromine especially fluorine and chlorine.
  • Examples include trifluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, chloromethyl, bromomethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-chloro-2, 2-difluoroethyl, pentafluoroethyl and pentafluoro-tert-butyl called.
  • Optionally substituted alkoxy alone or as part of a radical in the general formulas means straight-chain or branched alkoxy with preferably 1 to 6, in particular 1 to 4, carbon atoms. Substituted methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy may be mentioned as examples.
  • Optionally substituted alkoxyalkoxy alone or as part of a radical in the general formulas means straight-chain or branched alkoxyalkoxy with preferably 1 to 6, in particular 1 to 4, carbon atoms. Substituted methoxymethoxy, methoxyethoxy, methoxy-n-propoxy and ethoxyisopropoxy may be mentioned as examples.
  • Optionally substituted alkoxyalkoxyalkoxy alone or as part of a radical in the general formulas means straight-chain or branched alkoxyalkoxyalkoxy with preferably 1 to 6, in particular 1 to 4, carbon atoms. Substituted methoxymethoxyethoxy, methoxyethoxyethoxy and methoxyethoxy-n-propoxy may be mentioned as examples.
  • Optionally substituted haloalkoxy alone or as part of a radical in the general formulas means straight-chain or branched haloalkoxy with preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples include optionally substituted difluoromethoxy, trifluoromethoxy, trichloromethoxy,
  • Chlorodifluoromethoxy 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1, 1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy and 2-chloro-l, l, 2-trifluoroethoxy.
  • Optionally substituted alkylthio alone or as part of a radical in the general formulas means straight-chain or branched alkylthio with preferably 1 to 6, in particular 1 to 4, carbon atoms.
  • Examples of optionally substituted methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio and tert-butylthio may be mentioned.
  • Optionally substituted haloalkylthio alone or as part of a radical in the general formulas means straight-chain or branched haloalkylthio with preferably 1 to 6, in particular 1 to 4, carbon atoms.
  • Examples include optionally substituted difluoromethylthio, trifluoromethylthio, trichloromethylthio, chlorodifluoromethylthio, 1-fluoroethylthio, 2-fluoroethylthio, 2,2-difluoroethylthio, 1, 1, 2,2-tetrafluoroethylthio, 2,2,2-trifluoroethylthio and 2-chloro - 1, 1, 2-trifluoroethylthio called.
  • Optionally substituted alkylcarbonyl alone or as part of a radical in the general formulas means straight-chain or branched alkylcarbonyl having preferably 1 to 6, in particular 1 to 4, carbon atoms.
  • Examples of optionally substituted methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, sec-butylcarbonyl and tert-butylcarbonyl may be mentioned.
  • Optionally substituted cycloalkylcarbonyl alone or as part of a radical in the general formulas means mono-, bi- and tricyclic cycloalkylcarbonyl, preferably having 3 to 10, in particular 3, 5 or 7, carbon atoms.
  • Examples include optionally substituted cyclopropylcarbonyl, cyclobutyl carbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, bicyclo [2.2.1] heptylcarbonyl, bicyclo [2.2.2] octylcarbonyl and adamantylcarbonyl.
  • Optionally substituted alkoxycarbonyl alone or as part of a radical in the general formulas means straight-chain or branched alkoxy with preferably 1 to 6, in particular 1 to 4, carbon atoms.
  • Examples of optionally substituted methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl may be mentioned.
  • Aryl is, for example, a mono-, di- or polynuclear aromatic radical such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, fluorenyl and the like, but preferably phenyl or naphthyl.
  • Optionally substituted aryl in the general formulas preferably means optionally substituted phenyl or naphthyl, especially phenyl.
  • Optionally substituted arylalkyl in the general formulas preferably means arylalkyl optionally substituted in the aryl part and / or alkyl having preferably 6 or 10, in particular 8 carbon atoms in the aryl part (preferably phenyl or naphthyl, in particular phenyl) and preferably 1 to 4, in particular 1 or 2 Carbon atoms in the alkyl part, where the alkyl part can be straight-chain or branched.
  • optionally substituted benzyl and 1-phenylethyl may be mentioned.
  • the optionally substituted radicals of the general formulas can carry one or more, preferably 1 to 3, in particular 1 to 2 identical or different substituents.
  • Examples of preferred substituents are:
  • the number of these substituents is not limited, it is preferably one to four identical or different substituents.
  • the presence of two identical or different substituents on the same atom or on atoms of cyclic amino groups is also conceivable
  • Optionally substituted mono- or dialkylamino groups alone or as part of a radical in the general formulas means straight-chain or branched alkyl having preferably 1 to 6, in particular 1 to 4, carbon atoms.
  • Examples of substituted mono- or dialkylamino groups are methylamino,
  • Ethylamino, Dimethylamino, Diethylamino, Di-n-propylamino, Diisopropylamino or Dibutylamino called
  • Optionally substituted mono- or dialkoxyalkylamino groups alone or as part of a radical in the general formulas means straight-chain or branched alkoxyalkyl having preferably 1 to 6, in particular 1 to 4 carbon atoms. Examples of substituted mono- or dialkoxyalkylamino groups are
  • Methoxymethylamino Methoxyethylamino, D ⁇ - (methoxymethyl) -am ⁇ no or Di- (methoxyethyl) -ammo
  • Suitable cyclic amino groups are heteroaromatic or aliphatic ring systems with one or more nitrogen atoms as the heteroatom, in which the heterocycles can be saturated or unsaturated, one ring system or more condensed ring systems, and optionally further heteroatoms such as one or two nitrogen, oxygen and sulfur
  • cyclic amino groups can also mean a spiral or bridged ring system.
  • the number of atoms which form cyclic amino groups is not limited, for example they consist of 3 to 8 atoms in the case of a single-ring system and 7 to 11 atoms in the case of a three-ring system
  • cyclic amino groups with saturated and unsaturated monocyclic groups with a nitrogen atom as hetero atom are 1-azetidinyl,
  • Examples of cyclic amino groups with saturated and unsaturated monocyclic groups with two or more nitrogen atoms as heteroatoms are 1-Imtdazol ⁇ d ⁇ nyl, 1-Im ⁇ dazolyl, 1-pyrazolyl , 1-t ⁇ azolyl, 1-tetrazolyl, 1-p ⁇ peraz ⁇ nyl, 1-homop ⁇ perazmyl, 1,2-d ⁇ hydro-py ⁇ daz ⁇ n-l-yl, 1,2-d ⁇ hydro-py ⁇ m ⁇ d ⁇ n-1-yl, perhydropy ⁇ m ⁇ d
  • Groups include 2-azasp ⁇ ro [4,5] decan-2-yl, and 2-azab ⁇ cyclo [2,2, l] - heptan-7-yl is an example of cyclic amino groups with bridged heterocyclic groups
  • Suitable amm protecting groups are acyl groups, preferably having 1 to 6, in particular 1 to 4, carbon atoms, such as, for example, formyl, acetyl, propionyl, pivaloyl, hexanoyl or mono- (or di- or t ⁇ -) halogen-containing acyl groups, such as chloroacetyl , Bromoacetyl, dichloroacetyl and trifluoroacetyl, alkoxycarbonyl group preferably having 1 to 14, in particular 1 to 4 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl (Boc), tert-amyloxycarbonyl (Aoc), hexyloxycarbonyl, methylsulfonyleth- oxycarbonyl, adamantyloxycarbonyl (Adoc) and l- [l-adamantyl] -l-methyl
  • Suitable thiol protecting groups are optionally substituted alkyl groups having preferably 1 to 6, in particular 1 to 4, carbon atoms, such as, for example, acetamidomethyl and chloroacetamidomethyl, phenylalkyl-containing alkyl groups, such as, for example, benzyl, 4-methoxybenzyl, diphenylmethyl, triphenylmethyl and
  • the protective groups mentioned above have the function known in peptide chemistry of temporarily protecting amino, hydroxyl or thiol groups of compounds
  • R, R, R and R ⁇ represent Ci 4 alkyl, in particular methyl, R 2 , R 5 , R 8 and R are C M alkyl, in particular isobutyl,
  • R 3 and R 9 are C - alkyl, in particular methyl
  • R 6 and R 12 independently of one another for C - alkyl, in particular methyl, hetaryl -CC. 2 -alkyl, in particular benzozhiazol-2-yl-methyl, alkoxy carbonylmethyl, in particular diphenylmethoxycarbonylmethyl and for optionally substituted benzyl, where hydrogen, halogen, in particular bromine, fluorine, chlorine or iodine, cyano, carbamoyl, C M are mentioned as substituents - Alkyl, especially methyl, hydroxyl or hydroxyl, C ⁇ _ 8 - alkoxy, especially methoxy, ethoxy, n-propyloxy, isopropyloxy, butyloxy, tert-butyloxy, octyloxy or triphenylmethoxy, C].
  • 6 -alkylamino-C ⁇ .6-alkoxy especially 2-N-methylamino-ethoxy, N, N-di-C ⁇ _ 6 -alkylamino-C ⁇ .6-alkoxy, especially N, N-di-ethylamino-methoxy , 2-N, N-dimethylamino-ethoxy or 2-N, N-diethylamino-ethoxy, N, N-di - [(C ⁇ . 6 -alkoxy-C ⁇ . 6 -alkyl)] amino-C ⁇ .
  • C 3 . 7 -cycloalkylamino- (where one or more nitrogen atoms are present as ring-forming atoms and furthermore oxygen or sulfur atoms can be contained) -C ⁇ .6-alkoxy, especially 2-N-morpholino-ethoxy, 2-N-piperidino-ethoxy, pyrrolidinomethoxy, C 3 . 7- Cyclo-alkylamino (where one or more nitrogen atoms are present as ring-forming atoms and oxygen or sulfur atoms may also be present), in particular N-morpholino, N-thiomorpholino, piperidino, C 3 .
  • X 1 means sulfur
  • X 2 , X 3 and X 4 independently of one another denote oxygen or sulfur
  • X, X and X 4 independently of one another denote oxygen or sulfur
  • X, X and X independently of one another denote oxygen or sulfur
  • X 1 , X 2 and X 3 independently of one another denote oxygen or sulfur
  • R 1 , R 4 , R 7 and R 10 are methyl
  • R 2 , R 5 , R 8 and R 11 represent isobutyl
  • R and R represent methyl, R represents unsubstituted benzyl,
  • R represents substituted benzyl
  • substituents in the para position of the phenylrmges are hydrogen, C ⁇ _8-alkoxy, especially methoxy, tert-butyloxy, hetaryl-Ci . - alkoxy, in particular fur-2-yl-methoxy, tetrahydro
  • substituents in the para position of the phenylrmges are hydrogen, C ⁇ _8-alkoxy, especially methoxy, tert-butyloxy, hetaryl-Ci . - alkoxy, in particular fur-2-yl-methoxy, tetrahydro
  • N-Boc-pyrrole-2-yl-methoxy py ⁇ d-2-yl-methoxy
  • pyrrole-d-2-yl-methoxy 5- sec-butyl-1, 2,4-oxad ⁇ azol-3-yl-methoxy, 5-cyclopropyl-1, 2,4-oxad ⁇ azol-3-yl-meth
  • X 1 means sulfur, X, X and X independently of one another denote oxygen or sulfur,
  • X 2 means sulfur
  • X 1 , X 3 and X 4 independently of one another denote oxygen or sulfur
  • X 1 , X 2 and X 4 independently of one another denote oxygen or sulfur
  • X 1 , X 2 and X 3 independently of one another denote oxygen or sulfur
  • R 1 , R 4 , R 7 and R 10 are methyl
  • R 2 , R 5 , R 8 and R u represent isobutyl
  • R 3 and R 9 represent methyl
  • R 6 and R 12 each represent the same substituted benzyl
  • substituents in the para position of the phenyl ring are hydrogen, Ci-s-alkoxy, especially methoxy, tert-butyloxy, hetaryl -CC. 4 - alkoxy, especially fur-2-yl-methoxy, tetrahydro
  • N-boc-pyrrolidin-2-yl-methoxy pyrid-2-yl-methoxy
  • pyrrolidin-2-yl-methoxy 5-sec - Butyl-l, 2,4-oxadiazol-3-yl-methoxy
  • 5-cyclopropyl-l, 2,4-oxadiazol-3-yl-methoxy imidazol-5-yl-methoxy, nitro, amino, N, N -Di-C ⁇ .
  • 6 -alkylamino-C ⁇ . 6 - alkoxy in particular N, N-diethylamino-methoxy or 2-N, N-diethylamino-ethoxy, N, N-di - [(C ⁇ .6-alkoxy-C ⁇ - 6 -alkyl)] amino-C ⁇ - 6 - alkoxy, especially 2- [N, N-di (methoxyethyl) amino] ethoxy, C ⁇ .4-dialkylamino, especially dimethylamino, C 3 .
  • X 2 , X 3 and X 4 independently of one another denote oxygen or sulfur
  • X 2 means sulfur
  • X 1 , X 3 and X 4 independently of one another denote oxygen or sulfur, or
  • X 3 S S ⁇ sulfur means X 1 , X 2 and X 4 independently of one another are oxygen or sulfur,
  • X 1 , X 2 and X 3 independently of one another denote oxygen or sulfur
  • R 1 , R 4 , R 'and R' ⁇ are methyl, R 2 , R 5 , R 8 and R 11 represent isobutyl,
  • R 3 and R 9 represent methyl
  • R 6 represents unsubstituted benzyl
  • R 12 represents substituted benzyl
  • N-Boc-pyrrolidin-2-yl-methoxy pyrid-2- yl-methoxy
  • pyrrolidin-2-yl-methoxy 5-sec-butyl-l, 2,4-oxadiazol-3-yl-methoxy
  • X, X and X independently of one another denote oxygen or sulfur
  • X 1 , X ⁇ and X 4 independently of one another denote oxygen or sulfur
  • X 3 means sulfur
  • X 1 , X 2 and X 4 independently of one another denote oxygen or sulfur
  • X 4 denotes sulfur
  • X 1 , X 2 and X 3 independently of one another denote oxygen or sulfur
  • R 1 , R 4 , R 7 and R 10 are methyl
  • R 2 , R 5 , R 8 and R 11 represent isobutyl
  • R 3 and R 9 represent methyl
  • R 6 and R 12 each represent the same substituted benzyl
  • substituents in the para position of the phenyl ring are hydrogen, -CC-8-alkoxy, in particular tert-butyloxy, hetaryl-C M-alkoxy, in particular fur-2-yl-methoxy, tetrahydro
  • 6 - alkoxy in particular 2-N, N-diethylaminoethoxy, N, N-di - [(C ⁇ . -Alkoxy-C ⁇ . 6 - alkyl)] - ⁇ -C ⁇ - 6 alkoxy, especially 2- [N, N-D ⁇ (methoxyethyl) am ⁇ no] - ethoxy, C ⁇ . -D ⁇ alkylam ⁇ no, especially dimethylamino, C 3 7 -cycloalkyl-amino- (where as ring-forming atoms contain one or more nitrogen atoms and may also contain oxygen or sulfur atoms) -C ⁇ . 6 -alkoxy, in particular 2-N-morpholine-ethoxy, C 3 . 7- cycloalkylamino- (where one or more nitrogen atoms are present as ring-forming atoms and oxygen or sulfur atoms may also be present), in particular N-morphohno,
  • X 1 means sulfur
  • X 2 , X 3 and X 4 independently of one another denote oxygen or sulfur
  • X 2 means sulfur.
  • X, X and X independently of one another denote oxygen or sulfur,
  • X 1 , X 2 and X 4 independently of one another denote oxygen or sulfur
  • X means sulfur
  • X 1 , X 2 and X 3 independently of one another denote oxygen or sulfur
  • the thiodepsipeptides of the general formula (I) to be used according to the invention and their salts also contain one or more chiral centers and can thus be present as pure stereoisomers or in the form of various mixtures of enantiomers and diastereomers which, if necessary, can be separated in a manner known per se or also by stereoselective reactions in combination with the use of stereochemically pure starting materials
  • optically active, stereoisomeric forms of the compounds of the general formula (I) and their salts are preferably used according to the invention.
  • the cyclic depsipeptides are particularly preferably used, which are composed of (S) -configured amino acids (L-form) and (R) -configured hydroxycarboxylic acids (D-form) as ring building blocks
  • the invention therefore relates both to the pure enantiomers and diastereomers and to their mixtures for controlling endoparasites, particularly in the field of medicine and veterinary medicine
  • Suitable non-toxic salts i.e. salts with different bases and salts with added, can be suitable salts of the thiodepsipeptides of the general formula (I)
  • salts with inorganic bases such as alkali metal salts, for example sodium, potassium or cesium salts, alkaline earth metal salts, for example calcium or magnesium salts, ammonium salts, salts with organic bases and with inorganic amines, for example triethylammonium, dicyclohexylammonium , N, NXDibenzylethylenediammonium, pyridinium, picolinium or ethanolammonium salts, salts with inorganic acids, for example hydrochlorides, hydrobromides, dihydrosulfates, trihydrosulfates, or phosphates, salts with organic carboxylic acids or organic sulfonic acids, for example formates, acetates, trifluoroacetates, trifluoroacetates Tartrates, methanesulfonates, benzenesulfonates or para-toluenesulfonates, salts with basic amino
  • Cyclo (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-4-nitro-phenylthio-lactyl-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L -leucinyl-D-4-nitro-phenylthio-lactyl-), Cyclo (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-4-nitro-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl -D-4-nitro-phenyllactyl-),
  • the compounds of the general formula (I) are new and can be prepared, for example, by the process indicated above.
  • the new thiodepsipeptides of the general formula (I) can be obtained by thionation of one or more amide groups from corresponding depsipeptides of the general formula (II).
  • the cyclic depsipeptide cyclo (-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl- N-methyl-L-leucinyl-D-phenyllactyl- (PF 1022A) as a compound of the general formula (II) and used as thionating agent, "Xawesson's Reagent", so the cyclo (-N-methyl-L-leucinyl -D-thiolactyl-N-methyl-L-leucinyl-D-phenylthiolactyl-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenyl-thiolactyl-
  • the cyclic depsipeptide cyclo (-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D is used -lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) (PF 1022A) as a compound of the general formula (II) and used as thionating agent, ßelleau's reagent ", the cyclo (-N-methyl) is formed selectively -L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-
  • R 1 to R 12 are preferably those radicals which are already preferred in connection with the description of the substances of the formula (I) according to the invention these substituents were called
  • cyclic depsipeptides used as starting materials are known in some cases and can be obtained by fermentation or total synthesis using methods known from the literature [cf. Fermentation of the cyclooctadepsipeptides PF 1022A fermentation from Mvcelia sterilia (FERM BP-2671; former name FERM P-10 504) in EP-OS 382 173, T. Sasaki et al, J. Antibiotics 45, 1992, S 692, US Pat.
  • H 2 S hydrogen sulfide
  • H 2 S / HC1 hydrogen sulfide / chlorine-hydrogen
  • H 2 S 2 / HC1 hydrogen persulfide / hydrogen chloride
  • polymeric ethyl aluminum sulfide [(EtAJS) n ] silicon disulfide (SiS 2 ), diborotrisulfide (BS 3 ), phosphorus pentachloride / dialuminium t ⁇ sulfide / sodium sulfate (PCl 5 / Al 2 S 3 / Na 2 SO 4 ), sodium sulfide / sulfuric acid
  • Davy reagent methyl (DR-Me), 2,4-bis (ethylthio) -l, 3,2,4-dthiadiphosphetane-2,4-disulfide "Davy reagent ethyl” (DR-Et), 2nd , 4-B ⁇ s- (p-toly_thio) -l, 3,2,4-d ⁇ th_ad ⁇ - phosphetane-2,4-disulfide "Davy reagent p-tolyl or Heimgartner reagent" (DR-T),
  • reaction sequences such as O-alkylation with R 3 O + BF 4 " (R -methyl, ethyl) (H Meerwein et al, Justus Liebigs Ann Chem 641,
  • Phosphorus reagents such as diphosphorus pentasulfide (PA), diphosphorus pentasulfide / pyridine (P 2 S 5 / Py), diphosphorus pentasulfide / triethylamine are preferred as sulfidation reagents for carrying out process 2 according to the invention
  • halogenated hydrocarbons in particular chlorinated hydrocarbons, such as tetrachlorethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichlorethylene, pentachloroethane, difluorobenzene, 1,2-dichloro-dichloro-benzene, chlorobenzene, chlorobenzene Chlorotoluene, trichlorobenzene; Alcohols such as methanol, ethanol, isopropanol, butanol; Ethers such as ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenetol, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dipropyl ether, diisoprop
  • Benzonitrile, m-chlorobenzonitrile and compounds such as tetrahydrothiophene dioxide and dimethyl sulfoxide, tetramethylene sulfoxide, dipropyl sulfoxide, benzylmethyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, diisoamyl sulfoxide; Sulfones such as dimethyl, diethyl, dipropyl, dibutyl, diphenyl, dihexyl, methylethyl, ethylpropyl, ethylisobutyl and pentamethylene sulfone; aliphatic, cycloaliphatic or aromatic hydrocarbons such as pentane, hexane, heptane, octane, nonane and technical hydrocarbons, for example so-called white spirits with components with boiling points in the range from 40 ° C to 250
  • the diluents to be used depend on the sulfurization reagent used in each case
  • preferred diluents for thionation are aromatic hydrocarbons such as benzene, toluene, chlorobenzene, bromobenzene, nitrobenzene or xylene, ethers such as ethyl propyl ether, methyl tert-butyl ether, anisole, phenetol, cyclohexyl methyl ether, tetrahydrofuran or dioxane
  • aromatic hydrocarbons such as benzene, toluene, chlorobenzene, bromobenzene, nitrobenzene or xylene
  • ethers such as ethyl propyl ether, methyl tert-butyl ether, anisole, phenetol, cyclohexyl methyl ether, tetrahydrofuran or dioxane
  • the thionation according to process 2 is carried out by the depsipeptides of the general formula (II) in the presence of a suitable sulfurizing reagent, for example [2,4-bis (4-methoxyphenyl) -2,4-dithioxo-l, 3,2, 4-dithiadiphosphetane
  • a suitable sulfurizing reagent for example [2,4-bis (4-methoxyphenyl) -2,4-dithioxo-l, 3,2, 4-dithiadiphosphetane
  • the reaction time is 10 minutes to 72 hours.
  • the reaction takes place at temperatures between -10 ° C and +200 ° C, preferably between 0 ° C and +150 ° C, particularly preferably at temperatures between +10 ° C and + 130 ° C or at the boiling point of a suitable diluent It is generally possible to work under normal pressure. Preferably one works at normal pressure or at pressures up to 15 bar and possibly under a protective gas atmosphere (nitrogen or helium).
  • a protective gas atmosphere nitrogen or helium
  • the entire reaction batch is cooled, separated from the thionating agent which precipitates and, if appropriate, washed.
  • the products obtained can be purified in the customary manner by recrystallization, vacuum distillation or column chromatography (see also the preparation examples).
  • thiodepsipeptides can be obtained from the individual building blocks with both (S) and (R) configurations (or L and D configurations) while maintaining the original configuration of the starting materials
  • inert solvents refer in each case to solvents which are inert under the respective reaction conditions but do not have to be inert under any reaction conditions
  • the active substances are suitable for combating pathogenic endoparasites which occur in humans and in animal husbandry and animal breeding in farm animals, breeding, zoo, laboratory, experimental and hobby animals. They are against all or individual developmental stages of the pests effective against resistant and normally sensitive species By fighting the pathogenic endoparasites disease, death and performance degradation (e.g. in the production of meat, milk, wool, skin, eggs, honey, etc.) are to be reduced, so that through the use of the active ingredients more economical and simple animal husbandry is possible.
  • pathogenic endoparasites disease e.g. in the production of meat, milk, wool, skin, eggs, honey, etc.
  • the pathogenic endoparasites include cestodes, trematodes, nematodes, acanthocephals, in particular From the order of the Pseudophylhdea, for example Diphylloboth ⁇ um spp, Spirometra spp, Schistocephalus spp, Ligula spp, Bothridium spp, Diphlogonoporus spp
  • Cyclophyllidea for example Mesocestoides spp, Anoplocephala spp, Paranoplocephala spp, Moniezia spp, 'Thysanosomsa spp, Thysamezia spp,
  • Gigantobilharzia spp Leucochlondium spp, Brachylaima spp, Echinostoma spp, Echinoparyphium spp, Echinochasmus spp, Hypoderaeum spp, Fasciola spp, Fas- ciohdes spp, Fasciolopsis spp, Cyclocoelum spp, Typhlocphotophonophonophonppin spp, Capplocphotomophon spp, Spp , Fischoede ⁇ us spp, Gastrothylacus spp, Notocotylus spp, Catatropis spp, Plagiorchis spp, Prosthogonimus spp, Dicrocoe um spp, Eurytrema spp, Troglotrema spp, Paragommus spp, Colly ⁇ clum spp, Nanophyppus sppis schis,
  • Strongy e.g. Strongylus spp, T ⁇ odontophorus spp
  • Oesophagodontus spp T ⁇ chonema spp, Gyalocephalus spp, Cylmdropharynx spp, Potenostomum spp, Cyclococercus spp, Cylicostephanus spp, Oesophagostomum spp, Chabertia spp, Stephanurus spp, Ancylostoma spp, Uncina ⁇ a spp, Bunostomum spp, Globocephalus spp, Syngamus spp, Cyathostoma spp, Metastrongylus spp, Dictyocaulus spp, Muelle ⁇ us spp, Protostrongylylusppppuspp, spp, Nepp spp, Elaphostrongylus spp, Parelaphostrongylus spp, Crenosoma spp, Paracrenosoma spp, Angiostrongylus spp, Ae
  • Oxyu ⁇ da From the order of the Oxyu ⁇ da, for example Oxyu ⁇ s spp, Enterobius spp, Passalurus spp, Syphacia spp, Aspiculuns spp, Heterakis spp
  • Asca ⁇ dia From the order of the Asca ⁇ dia, for example Asca ⁇ s spp, Toxasca ⁇ s spp, Toxocara spp, Parasca ⁇ s spp, Anisakis spp, Asca ⁇ dia spp
  • Filarnda e.g. Stephanofilana spp, Parafila ⁇ a spp, Seta ⁇ a spp, Loa spp, Dirofilaria spp, Litomosoides spp, Brugia spp, Wuchereria spp, Onchocerca spp
  • the livestock and breeding animals include mammals such as cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as mink, chinchilla, washable, birds such as chickens , Geese, turkeys,
  • Ducks, sweet and saltwater fish such as trout, carp, eels, reptiles, insects such as honeybee and silkworm
  • Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats
  • the pets include dogs and cats
  • the application can be prophylactic as well as therapeutic
  • the active ingredients are used directly or in the form of suitable preparations enterally, parenterally, dermally, nasally, by treating the environment or with the aid of shaped articles containing active ingredients such as strips, plates, bands, neck bands, ear tags, limb bands, marking devices
  • enteral application of the active ingredients takes place, for example, orally in the form of powder, tablets, capsules, pastes, drinks, granules, or oral solutions.
  • Suspensions and emulsions, boluses, medicated feed or drinking water takes place, for example, in the form of diving (dipping), spraying (spraying) or pouring on (pour-on and spot-on).
  • the parenteral application takes place, for example, in the form of injection ( intramuscular, subcutaneous, intravenous, intraperitoneal) or by implants
  • Solutions such as injection solutions, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, pour-on formulations, gels,
  • Formulations in which the active ingredient is processed in an ointment base or in a 01 in water or water in oil emulsion base Solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules, aerosols and inhalants, molded articles containing active ingredients
  • Injection solutions are administered intravenously, intramuscularly and subcutaneously
  • Injection solutions are prepared by dissolving the active ingredient in a suitable solvent and possibly adding additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives.
  • additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives.
  • the solutions are sterile filtered and filled
  • Physiologically acceptable solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerin, propylene glycol, polyethylene glycols, N-methyl-pyrrolidone, and mixtures thereof
  • the active ingredients can optionally also be dissolved in physiologically acceptable vegetable or synthetic oils which are suitable for injection
  • solution mediators solvents which require the active ingredient to dissolve in the main solvent or prevent it from precipitating out.
  • solvents which require the active ingredient to dissolve in the main solvent or prevent it from precipitating out.
  • examples are polyvinylpyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters
  • Preservatives are 'benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester, n-butanol
  • Oral solutions are used directly. Concentrates are administered orally after prior dilution to the application concentration. Oral solutions and concentrates are prepared as described above for the injection solutions, whereby sterile work can be dispensed with Solutions for use on the skin are dripped on, spread on, rubbed in, sprayed on or sprayed on. These solutions are prepared as described above for the injection solutions
  • Thickeners are inorganic thickeners such as bentonites, colloidal silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates
  • Gels are applied or spread onto the skin or placed in body cavities. Gels are produced by adding enough thickening agent to solutions that have been prepared as described for the injection solutions so that a clear mass with an ointment-like consistency is produced used thickener specified above
  • pour-on formulations are prepared by dissolving, suspending or emulsifying the active substance in suitable skin-compatible solvents or solvent mixtures. If necessary, other auxiliaries such as dyes, absorption-promoting substances, antioxidants, light stabilizers and adhesives are added.
  • Solvents that may be mentioned are water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycols, aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzylbenzoate, ethers such as alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol acyl monoethyl ether , Methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethyl acetamide, N-methylpyrrohdon, 2,2-dimethyl-4-oxy-methylene-l, 3-dimoxolane Dyes are all dyes approved for use on animals, which can be dissolved or suspended
  • Absorption-promoting substances are, for example, DMSO, spreading oils such as isopropyl mypstat, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols
  • Antioxidants are sulfites or metabisulfites such as potassium metabisulfite, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol
  • Light stabilizers are, for example, novantisol acid
  • Adhesives include cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin
  • Emulsions can be used orally, dermally or as injections
  • Emulsions are either type water in 01 or type 01 in water
  • Paraffinols, silicone oils, natural vegetable oils such as sesamol, almond oil, castor oil, synthetic triglycerides such as caprylic / capric acid biglyceride, triglyceride mixture with vegetable fatty acids of the chain length Cg_i 2 or other specially selected natural fatty acids, partial glycerol or unsaturated, saturated mixtures may be mentioned as the hydrophobic phase (ole) also hydroxyl-containing fatty acids, mono- and diglycerides of Cg / Ci Q fatty acids
  • Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols of the chain length Ci g-cig, isopropyl myristate, isopropyl palmitate, caprylic ester of fatty alcohols from capryl / caprine
  • Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol
  • Fatty acids such as oleic acid and their mixtures
  • hydrophilic phase Water, alcohols such as propylene glycol, glycerin, sorbitol and their mixtures may be mentioned as the hydrophilic phase
  • Non-ionic surfactants may be mentioned as emulsifiers, for example polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glyceryl monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether,
  • ampholytic surfactants such as di-Na-N-lauryl- ⁇ -iminodipropionate or lecithin,
  • anionic surfactants such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphate ester monoethanolamine salt
  • auxiliaries which may be mentioned are substances which increase viscosity and stabilize the emulsion, such as carboxymethyl cellulose, methyl cellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols Waxes, colloidal silica or mixtures of the listed substances
  • Suspensions can be used orally, dermally or as an injection. They are produced by suspending the active ingredient in a carrier liquid, if necessary with the addition of other auxiliaries such as wetting agents, dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers
  • surfactants specified above may be mentioned as wetting agents (dispersants)
  • Semi-solid preparations can be administered orally or dermally. They differ from the suspensions and emulsions described above only by their higher viscosity
  • the active ingredient is " mixed with suitable carriers, optionally with the addition of auxiliaries, and brought into the desired shape
  • Inorganic and organic substances serve as such.
  • Inorganic substances are, for example, common salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicas, clays, precipitated or colloidal silicon dioxide, phosphates
  • Organic substances are, for example, sugar, cellulose, food and feed such as milk powder, animal meal, cereal meal and meal, starches
  • Excipients are preservatives, antioxidants, dyes, which have already been listed above
  • suitable auxiliaries are lubricants and lubricants such as, for example, magnesium stearate, stearic acid, talc, bentonite, substances which promote decay, such as starch or crosslinked polyvinylpyrrolidone, binders, such as starch, gelatin or linear polyvinylpyrrolidone, and dry binders such as microcrystalline cellulose.
  • the active substances can also be present in the preparations in a mixture with synergists or with other active substances which act against pathogenic endoparasites.
  • Such agents are e.g. L-2,3,5,6-tetrahydro-6-phenylimidazothiazole, benzimidazole carbamate, praziquantel, pyrantel, febantel.
  • Ready-to-use preparations contain the active ingredient in concentrations of 10 ppm to 20 percent by weight, preferably 0.1 to 10 percent by weight.
  • Preparations which are diluted before use contain the active ingredient in concentrations of 0.5-90% by weight, preferably 5-50% by weight.
  • mice are experimentally infected with nematodes of the species Heterakis spumosa.
  • 90 embryonic Heterakis spumosa eggs are administered orally to the mice.
  • the suspended active ingredients are administered orally and / or intraperitoneally on the 46th day after the infection.
  • mice are sectioned on the 54th day after infection.
  • the adult parasites in the colon and caecum are counted microscopically.
  • the success of treatment in the dose group is related to the untreated control group.
  • the efficiency is determined by quantitatively counting the worm eggs excreted in the faeces before and after the treatment.
  • a complete suspension of egg excretion after treatment means that the worms have been aborted or are so damaged that they no longer produce eggs (effective dose).
  • the remaining crude product is chromatographed over a silica gel column (silica gel 60 - Merck, particle size 0.04 to 0.063 mm) first with the eluent methylene chloride and then with the eluent cyclohexane acetone (3 1).

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Abstract

L'invention concerne des thiodepsipeptides cycliques, notamment des cyclothiodepsipeptides ayant entre 18 et 24 chaînons, des thiodepsipeptides cycliques de formule générale (I) et leurs sels, où R?1, R4, R7 et R10¿ désignent indépendamment l'un de l'autre hydrogène, alkyle C¿1?-C4 à chaîne linéaire ou ramifiée, R?2, R5, R8 et R11¿ désignent indépendamment l'un de l'autre hydrogène, alkyle C¿1?-C8 à chaîne linéaire ou ramifiée, alkényle C1-C8, cycloalkyle C3-C6, cycloalkyle C3-C6-alkyle C1-C2, aryle-alkyle C1-C2, hétaryle, alkyle C1-C2, aryle ou hétaryle qui peuvent éventuellement être substitués, R?9 et R10¿ désignent conjointement avec les atomes auxquels ils sont liés, un composé cyclique à 5 ou 6 chaînons, qui est éventuellement substitué, R?10 et R11¿ désignent conjointement avec les atomes auxquels ils sont liés, un composé cyclique à 5 ou 6 chaînons, pouvant éventuellement être interrompu par oxygène, soufre, sulfoxy ou sulfonyle et qui est éventuellement substitué, R3 et R9 désignent indépendamment l'un de l'autre hydrogène, alkyle C¿1?-C8 ou aryle-alkyle C1-C2, cycloalkyle C3-C6-alkyle C1-C2, R?6 et R12¿ désignent indépendamment l'un de l'autre hydrogène, alkyle C¿1?-C8 à chaîne linéaire ou ramifiée, alkényle C1-C8, cycloalkyle C3-C6, cycloalkyle C3-C6-alkyle C1-C2, aryle-alkyle C1-C2, hétaryle-alkyle C1-C2, aryle ou hétaryle, qui sont éventuellement substitués, et X?1, X2, X3 et X4¿ désignent indépendamment les uns des autres oxygène ou soufre, au moins un des restes X?1, X2, X3 et X4¿ devant désigner soufre. L'invention concerne en outre les isomères et les racémates de ces thiodepsipeptides.
PCT/EP1998/001628 1997-04-02 1998-03-20 Thiodepsipeptides pour lutter contre des endoparasites et procede simple permettant de les preparer WO1998043965A1 (fr)

Priority Applications (7)

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JP54110898A JP2001524952A (ja) 1997-04-02 1998-03-20 内部寄生虫を防除するためのチオデプシペプチドおよび同物質の製造方法
AU70388/98A AU731789B2 (en) 1997-04-02 1998-03-20 Thiodepsipeptides for controlling endoparasites and a process for their preparation
DE59807652T DE59807652D1 (de) 1997-04-02 1998-03-20 Thiodepsipeptide zur bekämpfung von endoparasiten und ein verfahren zu ihrer herstellung
US09/381,946 US6265537B1 (en) 1997-04-02 1998-03-20 Thiodepsipeptides for combating endoparasites and a method for producing the same
NZ338102A NZ338102A (en) 1997-04-02 1998-03-20 Thiodepsipeptides for combating endoparasites
EP98917025A EP0973756B1 (fr) 1997-04-02 1998-03-20 Thiodepsipeptides pour lutter contre des endoparasites et procede simple permettant de les preparer
HK00108376A HK1029114A1 (en) 1997-04-02 2000-12-22 Thiodepsipeptides for combating endoparasites and a method for producing the same

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DE19713626.5 1997-04-02
DE19713626A DE19713626A1 (de) 1997-04-02 1997-04-02 Neue Thiodepsipeptide zur Bekämpfung von Endoparasiten und ein einfaches Verfahren zu ihrer Herstellung

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KR (1) KR20000076392A (fr)
CN (1) CN1083445C (fr)
AU (1) AU731789B2 (fr)
DE (2) DE19713626A1 (fr)
ES (1) ES2195331T3 (fr)
HK (1) HK1029114A1 (fr)
NZ (1) NZ338102A (fr)
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WO1999067281A1 (fr) * 1998-06-24 1999-12-29 Bayer Aktiengesellschaft Cyclooctadepsipeptides substitues
WO2000076985A1 (fr) * 1999-06-11 2000-12-21 Bayer Aktiengesellschaft Cyclo-iminodepsipeptides et leur utilisation pour lutter contre les endoparasites
US6774166B1 (en) 1999-06-11 2004-08-10 Bayer Aktiengesellschaft Thermoplastic molding compounds
WO2019105871A1 (fr) 2017-11-29 2019-06-06 Bayer Aktiengesellschaft Hétérocycles contenant de l'azote utiles en tant que pesticides

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US6828302B1 (en) 1999-12-08 2004-12-07 Xcyte Therapies, Inc. Therapeutic uses of depsipeptides and congeners thereof
PT1438966E (pt) * 1999-12-08 2007-05-31 Cyclacel Pharmaceuticals Inc Uso de depsipéptidos e seus congéneres como imunosupressores para tratamento de doenças infecciosas, como uma doença autoimune, reacções alérgicas ou doença hiperproliferativa da pele.
DE19962145A1 (de) * 1999-12-22 2001-06-28 Bayer Ag Schädlingsbekämpfungsmittel/Depsipeptide
DE19962147A1 (de) * 1999-12-22 2001-06-28 Bayer Ag Schädlingsbekämpfungsmittel / PF 1022-221
ES2526614T3 (es) 2004-03-05 2015-01-13 Nissan Chemical Industries, Ltd. Compuesto de benzamida sustituida con isoxazolina y agente de control de organismos nocivos
DE102008030764A1 (de) 2008-06-28 2009-12-31 Bayer Animal Health Gmbh Kombination von Amidin-Derivaten mit cyclischen Depsipeptiden
DE102009012423A1 (de) 2009-03-10 2010-09-16 Bayer Animal Health Gmbh Zubereitung auf Ölbasis
DE102010064245A1 (de) 2010-12-28 2012-06-28 Bayer Animal Health Gmbh Makrocylischen Lactone und deren Verwendung und deren Kombinationen mit anderen Wirkstoffen
WO2012028556A1 (fr) 2010-08-31 2012-03-08 Bayer Animal Health Gmbh Lactones macrocycliques et leur utilisation et leurs combinaisons avec d'autres substances actives
SG10202103403SA (en) 2015-05-20 2021-05-28 Boehringer Ingelheim Animal Health Usa Inc Anthelmintic depsipeptide compounds
SG11201805368YA (en) 2015-12-28 2018-07-30 Merial Inc Anthelmintic depsipeptide compounds
EP3541789A1 (fr) 2016-11-16 2019-09-25 Boehringer Ingelheim Animal Health USA Inc. Composés depsipeptidiques anthelminthiques

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EP0503538A1 (fr) * 1991-03-08 1992-09-16 Meiji Seika Kaisha Ltd. Composition médicale contenant un dépepsipeptide cyclique ayant une activité anthelminthique
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WO1996011945A2 (fr) * 1994-10-18 1996-04-25 Bayer Aktiengesellschaft Procede de sulfonylation, de sulfenylation et de phosphorylation de depsipeptides cycliques
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EP0382173A2 (fr) * 1989-02-07 1990-08-16 Meiji Seika Kaisha Ltd. Substance PF 1022, procédé pour sa préparation et composition anthelmintique contenant cette substance
EP0503538A1 (fr) * 1991-03-08 1992-09-16 Meiji Seika Kaisha Ltd. Composition médicale contenant un dépepsipeptide cyclique ayant une activité anthelminthique
EP0634408A1 (fr) * 1992-03-17 1995-01-18 Fujisawa Pharmaceutical Co., Ltd. Derive de depsipeptide, production et utilisation
EP0685469A1 (fr) * 1993-02-19 1995-12-06 Meiji Seika Kaisha Ltd. Derive du pf 1022 utilise comme depsipeptide cyclqiue
EP0626376A1 (fr) * 1993-05-26 1994-11-30 Bayer Ag Octacyclodepsipeptides ayant une activité endoparasiticide
EP0626375A1 (fr) * 1993-05-26 1994-11-30 Bayer Ag Octacyclodepsipeptides ayant une activité endoparasiticide
EP0718293A1 (fr) * 1993-09-06 1996-06-26 Fujisawa Pharmaceutical Co., Ltd. Compose de cyclodepsipeptide
WO1996011945A2 (fr) * 1994-10-18 1996-04-25 Bayer Aktiengesellschaft Procede de sulfonylation, de sulfenylation et de phosphorylation de depsipeptides cycliques

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WO1999067281A1 (fr) * 1998-06-24 1999-12-29 Bayer Aktiengesellschaft Cyclooctadepsipeptides substitues
WO2000076985A1 (fr) * 1999-06-11 2000-12-21 Bayer Aktiengesellschaft Cyclo-iminodepsipeptides et leur utilisation pour lutter contre les endoparasites
AU768501B2 (en) * 1999-06-11 2003-12-11 Bayer Aktiengesellschaft Cyclo-imino depsipeptides and their utilization in controlling endoparasites
US6774166B1 (en) 1999-06-11 2004-08-10 Bayer Aktiengesellschaft Thermoplastic molding compounds
WO2019105871A1 (fr) 2017-11-29 2019-06-06 Bayer Aktiengesellschaft Hétérocycles contenant de l'azote utiles en tant que pesticides

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HK1029114A1 (en) 2001-03-23
AU7038898A (en) 1998-10-22
CN1259128A (zh) 2000-07-05
DE59807652D1 (de) 2003-04-30
JP2001524952A (ja) 2001-12-04
US6265537B1 (en) 2001-07-24
KR20000076392A (ko) 2000-12-26
DE19713626A1 (de) 1998-10-08
NZ338102A (en) 2001-02-23
AU731789B2 (en) 2001-04-05
CN1083445C (zh) 2002-04-24
EP0973756B1 (fr) 2003-03-26
EP0973756A1 (fr) 2000-01-26
ES2195331T3 (es) 2003-12-01

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